The prevalence of obesity in both children and adults is on the rise in first world countries, especially in the United States, as well as in many developing countries such as China and India. Many aspects of a person's life are affected by obesity, from physical problems such as knee and ankle joint deterioration, to emotional problems resulting from self-esteem issues and society's attitude towards heavy people. The medical problems caused by obesity can be serious and often life-threatening and include diabetes, shortness of breath and other respiratory problems such as asthma and pulmonary hypertension, gallbladder disease, dyslipidemia (for example, high cholesterol or high levels of triglycerides) and dyslipidemic hypertension, osteoarthritis and other orthopedic problems, reflux esophagitis (heartburn), snoring, sleep apnea, menstrual irregularities, infertility, problems associated with pregnancy, gout, cardiovascular problems such as coronary artery disease and other heart trouble, muscular dystrophy, and metabolic disorders such as hypoalphalipoproteinemia, familial combined hyperlipidemia, and Syndrome X, including insulin-resistant Syndrome X. In addition, obesity has been associated with an increased incidence of certain cancers, notably cancers of the colon, rectum, prostate, breast, uterus, and cervix.
Obesity substantially increases the risk of morbidity from hypertension, dyslipidemia, type II diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis and endometrial, breast, prostate, and colon cancers. Higher body weights are also associated with increases in all-cause mortality. Many of these problems are relieved or improved when the afflicted individual undergoes permanent significant weight loss. Weight loss in these individuals can also promote a significant increase in longevity.
Strategies for treating obesity and related disorders have included dietary restriction, increased physical activity, pharmacological approaches, and even surgery, with the choice depending, at least in part, on the degree of weight loss one is attempting to achieve as well as on the severity of obesity exhibited by the subject. For example, treatments such as a low-calorie, low-fat diet and/or regular exercise are often adequate with individuals who are only mildly overweight. The difficulty in maintaining long-term weight loss through diet and behavior modification, however, has led to an increasing interest in other avenues for treatment, particularly pharmacotherapy.
Traditional pharmacological interventions typically induce a weight loss of between five and fifteen kilograms; if the medication is discontinued, renewed weight gain often ensues. Surgical treatments are comparatively successful and are reserved for patients with extreme obesity and/or with serious medical complications.
The above treatments can be enhanced by controlled use of over-the-counter appetite suppressants including caffeine, ephedrine and phenylpropanolamine (Acutrim®, Dexatrim®). Moreover, prescription medications including amphetamine, diethylpropion (Tenuate®), mazindol (Mazanor®, Sanorex®), phentermine (Fastin®, Ionamin®), phenmetrazine (Preludin®), phendimetrazine (Bontrol®, Plegine®, Adipost®, Dital®, Dyrexan®, Melfiat®, Prelu-2®, Rexigen Forte®), benzphetamine (Didrex®) and fluoxetine (Prozac®) are often used in the treatment of seriously overweight and/or obese subjects or patients.
While society has seen tremendous advances in the field of pharmaceuticals, there are, of course, drawbacks to the administration of any given pharmaceutical agent. Sometimes, the disadvantages, or “side effects,” are so severe as to preclude administration of a particular agent at a therapeutically effective dose. Furthermore, many agents in the same therapeutic class display similar side effect profiles, meaning that patients either have to forego therapy or suffer from varying degrees of side effects associated with the medication of choice.
In U.S. Pat. No. 7,056,890 to Najarian and U.S. Patent Publication Nos. US 2006/0234950 A1, US 2006/0234951 A1, and US 2006/0234952 A1 to Najarian, all of common assignment herewith to Vivus, Inc. (Mountain View, Calif.), a combination therapy for treating obesity and effecting weight loss is provided wherein a synergistic effect between the active agents enables dose reduction and a concomitant alleviation of side effects typically associated with each active agent. One of the active agents is an anti-convulsant agent, e.g., topiramate, and the second active agent is a sympathomimetic agent, typically a sympathomimetic amine such as phentermine. In U.S. patent application Ser. No. 12/135,935, also of common assignment herewith, an escalating dosing regimen is described for administering topiramate alone or in combination with a second therapeutic agent such as phentermine, wherein the second agent is selected so as to directly or indirectly reduce the side effects associated with one or both of the agents administered. By “indirectly” reducing side effects is meant that a first pharmaceutical agent allows the second agent to be administered at a lower dose without compromising therapeutic efficacy, thus reducing dose-dependent unwanted effects.
Topiramate (2,3,4,5-bis-O-(1-methylethylidene)-(3-D-fructopyranose sulfamate) is a broad-spectrum neurotherapeutic agent approved by the FDA and the regulatory agencies of many other countries for the treatment of certain seizure disorders and the prevention of migraine headaches. E. Faught et al. (1996) Neurology 46:1684-90; Karim et al. (1995) Epilepsia 36 (54):33; S. K. Sachdeo et al. (1995) Epilepsia 36 (54):33; T. A. Glauser (1999) Epilepsia 40 (55):571-80; R. C. Sachdeo (1998) Clin. Pharmacokinet 34:335-346). There has also been evidence that topiramate is effective in the treatment of diabetes (U.S. Pat. Nos. 7,109,174 and 6,362,220), neurological disorders (U.S. Pat. No. 6,908,902), depression (U.S. Pat. No. 6,627,653), psychosis (U.S. Pat. No. 6,620,819), headaches (U.S. Pat. No. 6,319,903) and hypertension (U.S. Pat. No. 6,201,010). However there have been adverse effects associated with the use of topiramate in humans, such as cognitive dulling and word finding difficulties, which can discourage many obese patients from taking this drug.
Phentermine was approved by the FDA as an appetite suppressant in 1959, and phentermine hydrochloride has been used as a weight loss agent since the 1970s, e.g., under the brand names Adipex-P®, Fastin®, Zantril®, and others. Although the FDA warned against combining phentermine with a second active agent following the reports of cardiac and pulmonary problems associated with the “Fen-Phen” product (in which phentermine was combined with fenfluramine, and later with a related drug, dexfenfluramine), it has since been found that a safe and effective weight loss treatment is provided by combining phentermine with an active agent that mitigates phentermine's side effects and enables administration of a much lower dose of phentermine than in “Fen-Phen” (containing 30 mg or 37.5 mg phentermine hydrochloride). See U.S. Pat. No. 7,056,890 to Najarian and U.S. Patent Publication Nos. US 2006/0234950 A1, US 2006/0234951 A1, and US 2006/0234952 A1 to Najarian, cited above.
It has now been discovered that a significantly lower dose combination product is effective in achieving weight loss, treating obesity, and treating conditions associated with obesity and excessive weight. The present invention is directed to this product and methods of using the product. The invention provides a number of important advantages vis-à-vis prior weight loss therapies, as will be described in detail herein.